Foiling Cancer Aggression — Nontoxic Metals
by Jackie Swift
Around 50 years ago, cancer treatment entered a new era with the implementation of the platinum-based chemotherapy drug Cisplatin. Once in the body, the platinum in the compound binds to and dramatically distorts DNA, inhibiting DNA transcription and replication in cells and causing cell death. There’s just one important catch: the platinum therapy is not targeted specifically to cancer cells.
“Like many chemotherapeutic drugs, the selectivity Cisplatin affords is generally poor,” says Justin J. Wilson, Chemistry and Chemical Biology at Cornell University. “It hinges on the fact that cancer cells divide much more rapidly than normal cells. So by targeting DNA, the drug affects the cancer cells that are dividing more rapidly rather than the noncancer cells which divide slower. That said, platinum chemotherapy gives rise to all sorts of toxic side effects.”
Finding the Right Metal
In an effort to advance the understanding of cancer treatment and find a better way to target cancer, Wilson has been investigating the biomedical application potentials of other heavy transition metals that have similar or slightly different properties than platinum. He is particularly interested in compounds of the element rhenium.
“Rhenium is located close to platinum on the periodic table,” Wilson says. “As a consequence, compounds of rhenium have a similar stability to platinum-based drugs, which we think is critically important. But the potential advantage of rhenium is that it has properties that can be imaged. We can make rhenium compounds that are luminescent. We can actually see in real time where they are going in a cell, what they’re targeting.”
While working with rhenium compounds, Wilson’s team — in collaboration with Shu-Bing Qian’s research group, Nutritional Sciences — discovered a class of rhenium complexes that induce cell death by causing endoplasmic reticulum (ER) stress. The ER is an organelle in cells that is responsible for folding proteins and carrying out regulatory functions.
“We created a compound that we found causes a huge amount of unfolded proteins in the cell,” Wilson says. “The cell can’t keep up with all the unfolded proteins, so it dies. That’s interesting in the context of the selectivity issue because cancer cells exist in a basal state of ER stress. They already have a much higher burden of unfolded proteins than normal noncancer cells.”
Wilson and his colleagues hypothesize that the rhenium compound may be able to selectively hit the cancer cells that already have a higher state of ER stress, pushing them over into a cell death pathway while healthy cells remain under that pathway. Working with mice models, the researchers have treated tumors with the compound and found some delay in the tumor growth, but they were even more excited at the limited toxic side effects. “When we look at sections of organs after treatment with the rhenium compound, we don’t see a lot of the damaging effects that we do with Cisplatin, for example,” Wilson says. “We’re hopeful this is a step in the right direction.”
Radioactive Metal Ions for Cancer Treatment
Continuing their cancer-related work, the Wilson group is also looking at the use of radioactive metal ions to treat the disease. Collaborating with John W. Babich, Radiology, Weill Cornell Medicine, the researchers have focused on actinium-225, which emits a radioactive particle known as an alpha particle. “Alpha particles are much more massive than radioactive emissions, such as gamma photons and beta particles,” Wilson explains. “Although beta-emitting radiopharmaceutical agents have been clinically used for therapy, these types of radiation are like shooting a high-powered rifle through a wall: you cause a bullet-hole’s worth of damage to 10 or 15 walls. But alpha radiation is like shooting a short-range cannon ball. You might only get through two or three walls, but they’re completely knocked out.”
To create an actinium-based radiopharmaceutical, the researchers include a biological targeting vector — an antibody or peptide that binds with high specificity to certain receptors that are over-expressed on cancer cells — which will deliver the actinium-225 to the tumor. Then they glue the two together with a chelating agent.
“After 14 to 21 days, we can see all our radioactive activity localized in the tumor…We can oblate the tumor volume with a single dose of this compound.”
“The focus of our lab is on designing the chelating agent,” Wilson says. “You can think of it as a molecular cage that holds these radioactive metal ions tight, keeping them attached to the antibody or peptide. If it lets go in vivo, then the radioactive ions can go anywhere in the body and cause all sorts of havoc. They really have to stay with the targeting vector.”
Wilson and his collaborators have tested the compound on mice models bearing implanted prostate cancer tumors. “We delivered our radioactive actinium isotope to cancer cells that over-express a prostate-specific membrane antigen,” Wilson says. “After 14 to 21 days, we can see all our radioactive activity localized in the tumor. It’s actually a pretty effective means of stably delivering this isotope. We can oblate the tumor volume with a single dose of this compound.”
Radioactive Metal Ions for Cancer Imaging
Wilson is already taking the next steps in his quest to apply this technique to other radioactive metal ions for different biomedical applications. Together with Jonathan Engle (University of Wisconsin, Madison) and Eszter Boros (Stony Brook University), he has explored the use of the lanthanum-132 isotope for imaging. “The idea is, rather than using it to destroy the tumor, you inject a compound and see it light up in the presence of cancer,” Wilson says. “That lets you know the disease is present, and then you could follow up with therapeutic intervention.”
As an inorganic chemist focusing on metals, Wilson is a bit of an oddity in the field of biomedicine. “In a conventional sense, there’s not too much intersection between inorganic chemistry and medicinal chemistry,” he explains. But Wilson found the properties and chemical structures of inorganic chemistry fascinating as an undergrad and was drawn to identifying ways of applying them to human health problems. In the case of the radioactive isotope project, he and his lab are venturing into territory where few chemists go.
“You often have a disconnect in the field of nuclear medicine,” he says. “For example, a nuclear physicist might identify a certain isotope that they think is a good candidate for medical research because it has this much half-life or this type of decay properties. But then when they consult a chemist, they might find a lot of chemists don’t know the appropriate chemistry necessary to attach this radioactive metal ion to a chelating agent or to a targeting vector. Our lab is trying to bridge that gap.”